Pancreatic cancer is the fourth leading cause of cancer related deaths in the United States. The 5-year survival rate for pancreatic cancer patients is only 6%, indicating a critical need for an improved understanding of pancreatic cancer development and identification of new therapeutic targets. MYC is a protein that strongly contributes to cancer progression in a wide variety of tissues and regulates several cellular functions that are corrupted during cancer development. Importantly, loss of MYC function can lead to cancer cell death and decreased tumor formation in mouse tumor models. Studies of MYC function have identified a modified form of MYC that has increased stability and activity. This form is found at high levels in several cancer cell types and leads to uncontrolled cell growth. Importantly, MYC is activated downstream of several factors known to be deregulated in pancreatic cancer. Specifically, the KRAS pathway, which is constitutively on in ~95% of all pancreatic ductal tumors, has been shown to contribute to MYC activation in other cell types. The role of MYC in pancreatic cancer, however, is poorly understood. The overall goal of this proposal is to determine if KRAS-mediated activation of MYC significantly contributes to pancreatic tumor progression. To achieve this goal, the proposed aims will utilize a novel mouse model of pancreatic cancer, patient tissue, and pancreatic cancer cells to investigate how MYC alters the initiation and progression of pancreatic cancer. Specifically, Aim 1 will determine if combining aberrant KRAS and MYC activity in a novel mouse model recapitulates the hallmarks of human pancreatic disease. Aim 2, will identify the stage at which MYC transitions to the more stable, active form in both human and mouse tumors. Finally, Aim 3 will determine if activation of MYC significantly contributes to the transformation of normal pancreatic cells to cancer cells downstream of KRAS signals. Pancreatic cancer remains highly resistant to cancer therapies. Alterations in the KRAS pathway occur in the majority of pancreatic cancer patients, however developing successful clinical drugs that target this protein has been unsuccessful. The proposed research will increase our understanding of the pathways that drive pancreatic cancer downstream of KRAS and potentially identify the proteins that control the activating modification of MYC as therapeutic targets in pancreatic cancer.